Decalactones, method for making, and pharmaceuticals there from

ABSTRACT

A novel class of decalactones with the general formula (I) and their stereoisomers is disclosed. A method for the synthesis of the decalactones of general formula (I) and the use of the decalactones in pharmaceutical compositions is also described.

[0001] With its indeterminate number of organisms, such as the bryozoa, mollusca and porifera species, the ocean represents an important source of secondary metabolites. Their diversity and structural properties can be simulated with classical synthetic methods only at great expense. An above average number of these natural products have biological properties, which are worthwhile following up. Accordingly, they are of interest as potential active ingredients or as novel guiding structures for the development of pharmaceuticals.

[0002] The natural products, potentially present in marine sponges and the bacteria, fungi and protists, associated with them, have been discovered to only a slight extent. Because of their habitat, marine sponges require an efficient defense mechanism. It is therefore very likely that compounds, which are highly active biologically already in very low concentrations, can be isolated. Halichondrin, spongistatin 1, ocadaic acid as well as swinholide A are mentioned as examples of such compounds, which have been isolated successfully from sponges.

[0003] The multitude substances, present in extracts of the marine organisms mentioned, requires methods for rapidly and intensively differentiating between compounds, which are already known, and those, which are novel. In particular, the “LC triad” is available here which represents a coupling of HPLC with NMR, MS and CD (G. Bringmann et al., Anal. Chem. 70, 2805-2811, 1998 and G. Bringmann et al.,Anal. Chem. 71, 2678-2686, 1999). This method permits not only known substances to be determined directly from the extracts but also, under suitable circumstances, structures, as far as the absolute configuration, to be clarified.

[0004] The development of tumors is a fundamental disease of higher organisms in plants, animals and man. Indeed generally recognized multi-step model of carcinosis assumes that, due to the accumulation of several mutations in a single cell, the latter is changed to such an extent in its proliferation and a differentiation behavior, that finally, over benign intermediate stages, a malignant state with metastasizing is attained.

[0005] The concept of cancer or tumor harbors a syndrome with more than 200 different individual diseases. Tumor diseases may be benign or malignant. The most important tumors are in the lung, the breast, the stomach, the cervix, the prostate, the head and the neck, the large intestine and rectum, the liver and the blood system. There are large differences with respect to the progression, prognosis and therapy behavior. More than 90 percent of the cases recognized relate to solid tumors, which can be treated only with difficulty, if at all, especially in advanced stages or when there has been metastasizing.

[0006] The three pillars of combating cancer continued to be surgical removal, radiation and chemotherapy. Until now, it has not been possible to develop pharmaceuticals, which bring about unambiguous prolongations of survival times or even complete curing in the case of metastasizing, solid tumors. It is therefore meaningful to discover new pharmaceuticals for fighting carcinosis.

[0007] A new way of treating cancer is the prevention of signal conduction from a cell surface receptor in the nucleus of the cell by inhibiting specific enzymes. This biological activity can be brought about by synthetic materials and also by natural products.

[0008] The search for new anti-infective agents is also meaningful, since many diseases, brought about by infections, can be treated only inadequately, and increasingly, many protozoic and fungal organisms develop resistance against pharmaceuticals commonly used at the present time.

STATE OF THE ART

[0009] In the present invention, new decalactones are described as 10-membered macrolids with a fused 1, 3-dihydroxybenzene ring. These natural products were not synthesized previously or isolated from any biological source. 12-Membered macrolids of the curvularin type from terrestrial strains of Curvularia (O. C. Musgrave, J. Org. Chem., 4301-4305, 1956), Penicillium sp. (S. Lai, Y. Shizuri, S. Yamamura, K. Kawai, Y. Tearda and H. Furukuwa, Tetrahedron Lett., 2241-2244 (1989), Cochliobulus (E. L. Ghisalberti and C. Y. Rowland, J. Nat. Prod. 56, 2175-2177, 1993) and Altemaria (D. J. Roberson and G. A. Strobel, J. Nat. Prod., 48, 139-141, 1985) are described. Other decalactones were already isolated from fungi of the diplodia species (K. Wada and T. Ishida, J C S Perkin I, 1154-1158, 1979) and Penicillium (S. Lai, Y. Shizuri, S. Yamamura, K. Kawai, Y. Tearda and H. Furukuwa, Tetrahedron Lett., 2241-2244, 1989) and their action as steroid hydroxylase inhibitors was described. Likewise, structurally similar lactones occur in the pathogenic plant fungus Diplodia pinea (K. Wada and T. Ishida, J C S Perkin 1, 1154-1158, 1979) and as metabolites in the insect Phoracanta synonyma (B. P. Moore and W. V. Brown, Aust. J. Chem. 29, 1365-1369, 1976). However, the structure and properties of these decalactones differ from those of the compounds described in this invention.

SUMMARY OF THE INVENTION

[0010] The object of the invention is the isolation, structure clarification, synthesis and use of new biologically active decalactones from associated fungi of marine sponges and of the synthetic derivatives as pharmaceuticals. The compounds, described in the invention, are to be used as active components of pharmaceuticals. The pharmaceuticals can be used to combat diseases in man and animals.

[0011] The invention relates to new, biologically active decalactones from associated fungi of marine sponges, their synthesis, and their synthetic derivatives as pharmaceuticals.

[0012] The new compounds have the general Formula 1:

[0013] The compounds of Formula 1 may be present as R and S enantiomer, as (R,R), (S,S), (R,S) and (S,R) stereoisomers as well as in the form of all possible mixtures of stereoisomers.

[0014] The R¹ group may be hydrogen, a linear or branched C₁-C₆ alkyl, preferably methyl, C₁-C₆ alkyl, which is mono-substituted or multi-substituted by C₆-C₁₄ aryl, preferably benzyl, linear or branched carboxy C₁-C₁₈ alkyl, linear or branched C₁-C₆ alkoxycarbonyl, linear or branched C₁-C₁₂ alkylcarbonyl, preferably acetyl, C₂-C₆ alkenyl, preferably allyl, C₁-C₆ alkinyl, preferably ethinyl or propargyl, linear or branched cyano C₁-C₆ alkyl, preferably cyanomethyl or benzyloxy, 9-fluorenylmethoxy-carbonyl (Fmoc), triphenylmethyl (Tr), 2-(4′-pyridyl) ethoxycarbonyl (Pyroc) or diphenylmethylsilyl (DPMS).

[0015] The R² group may be hydrogen, a linear or branched C₁-C₆ alkyl, preferably methyl, C₁-C₆ alkyl, which is mono-substituted or multi-substituted by C₆-C₁₄ aryl, preferably benzyl, linear or branched carboxy C₁-C₁₈ alkyl, linear or branched C₁-C₆ alkoxycarbonyl, linear or branched C₁-C₁₂ alkylcarbonyl, preferably acetyl, C₂-C₆ alkenyl, preferably allyl, C₁-C₆ alkinyl, preferably ethinyl or propargyl, linear or branched cyano C₁-C₆ alkyl, preferably cyanomethyl or benzyloxy, 9-fluorenylmethoxy-carbonyl (Fmoc), triphenylmethyl (Tr), 2-(4′-pyridyl)ethoxycarbonyl (Pyroc) or diphenylmethylsilyl (DPMS).

[0016] X may be O, S, NOH, NOR⁴, in which R⁴ is linear branched C₁-C₆ alkyl, preferably methyl, which is mono-substituted or multi-substituted by C₆-C₁₄ aryl, preferably benzyl, linear or branches carboxy C₁-C₁₈ alkyl, linear or branched C₁-C₆ alkoxy carbonyl and linear or branched C₁-C₁₂ alkylcarbonyl, preferably acetyl.

[0017] Y maybe O or S.

[0018] The Z group may be H or OR³, in which R³ may be H, a linear or branched C₁-C₆ alkyl, preferably methyl, C₁-C₆ alkyl, which is mono-substituted or multi-substituted by C₆-C₁₄ aryl, preferably benzyl, linear or branched carboxy C₁-C₁₈ alkyl, linear or branched C₁-C₆ alkoxycarbonyl, linear or branched C₁-C₁₂ alkylcarbonyl, preferably acetyl, C₂-C₆ alkenyl, preferably allyl, C₁-C₆ alkinyl, preferably ethinyl or propargyl, linear or branched cyano C₁-C₆ alkyl, preferably cyanomethyl or benzyloxy, 9-fluorenylmethoxycarbonyl (Fmoc), triphenylmethyl (Tr), 2-(4′-pyridyl) ethoxycarbonyl (Pyoc) or diphenylmethylsilyl (DPMS).

[0019] In the case of the general Formula I, in which R¹ and R² represent H, X and Y represent O and Z represents H, the compound is named xestodecalatone A. In the case of the general Formula I, in which R¹, R² and R³ are H, X and Y are O and Z is OR³, the compounds are named xestodecalatone B or C, depending on the stereo chemistry.

[0020] The marine sponge Xestospongia exigua occurs in the Bali Ocean of Indonesia. This sponge was collected and the Penicillium sp. fungus was isolated from it. The fungus was cultured and, after on-line investigations of the extract with HPLC-MS/MS, HPLC-NMR and HPLC-CD, new natural products were isolated from the culture broth in the form of fungal metabolites. The new compounds isolated are named xestodecalatone A, B and C. The xestodecalatone A, B and C were converted by means of known chemical reactions into new chemical derivatives, which were previously not known.

[0021] The inventive compounds can be converted with known techniques into galenic forms of administration, which are suitable for therapeutic applications. Suitable galenic forms of administrations are ointments, drops, tablets, capsules, suppositories, forms suitable for injection, forms suitable for nasal administration and forms suitable for inhalation. The galenic forms of administration used can be used intravenously, intramuscularly, intradermally, subcutaneously, intraperitoneally, rectally, topically and intravenously in the form of liposomes.

[0022] The invention furthermore comprises a process for the synthesis of compounds of the general Formula I from a biological source. For this purpose, the Penicillium sp. fungus is isolated and cultured and compounds are isolated in a suitable manner from the culture broth and purified.

[0023] The invention furthermore comprises a process for the synthesis of compounds of the general Formula I from known chemical precursors by means of known chemical reactions. The invention consists of the meaningful combination of these reactions in accordance with the general synthesis procedure A.

[0024] General Synthesis Procedure A

[0025] The inventive compounds are to be used as pharmaceuticals for combating diseases in man or animals. The diseases may be cancers, disorders of the endocrine metabolism inflammatory diseases such as psoriasis, arthritis, Crohn's diseases or asthma. Moreover, the inventive compounds are to be used for the treatment of infectious diseases, such as fungal diseases or diseases due to plasmodia or trypanosomes.

[0026] The inventive compounds preferably act over the interactions of the endogenous proteins, cellular kinases or over hormone receptors, which affect cell metabolism or cell growth. The kinases may be receptors and enzymes of the signal processing cascade of the cell, such as receptor tyrosine, non-receptor tyrosine and serine threonine kinases. Hormone receptors may, for example, be receptors coupled around G protein. In addition, an interaction with proteins of the cellular cyto-skeleton is possible; tubulin is an example of this.

[0027] It may also be assumed that the claimed compounds act by a different biological mechanism, which was previously unknown. The inventive compounds furthermore are able to kill microorganisms.

EXAMPLES General Recovery of the Claimed Compounds from Biological Material

[0028] The claimed compounds are obtained from the mycelia and culture filtrate of a fungus. The fungus preferably is of the Penicillium sp. It is, however, also conceivable that the inventive compounds are isolated from other biological sources, especially from other strains of Penicillium.

[0029] The fungus of the Penicillium sp. occurs in association with a marine sponge. The sponge is Xestospongia exigua. It is, however, also conceivable that the fungus occurs in other marine sponges. The marine sponge Xestospongia exigua occurs in coastal waters of the island of Mengangan in the Bali Ocean of Indonesia. The marine sponge Xestospongia exigua, as a source of the fungus of the Penicillium sp., may also occur in other waters. Moreover, the fungus of the Pencillium sp. may also occur in other sponges.

[0030] It is furthermore conceivable to grow the marine sponge, which contains the fungus of the Penicillium sp., artificially in marine aquaculture.

[0031] The claimed compounds are isolated from the culture medium of the fungus of the Penicillium sp. by known methods. The fungus of the Penicillium sp. can also be reproduced and cultured artificially without a sponge.

[0032] A strain of the fungus of the Pencillium sp. with the register No. HBI-3 is kept at the Alfred Wegener Institute for Polar and Ocean Research in Bremerhaven.

[0033] Description of the General Method of Isolation

[0034] The fungus of the Pencillium sp. is isolated from freshly collected samples of the marine sponge Xestospongia exigua. The sponge is collected by diving. Tissue samples are obtained from a portion of the sponge and transferred to suitable culture medium. Preferably, agar is used. The incubation is carried out at temperatures between 25° and 32° C. The medium used contains nutrients, auxiliary materials and salts, preferably malt abstract and sea salt. The culture is reproduced in the usual manner and pure strains of the Penicillium sp. are isolated by re-inoculation on the nutrient medium. Before the extraction, the fungus is permitted to grow in a suitable medium, such as a molt broth medium. After a number of days of incubation, mycelia and culture filtrate are collected and extracted with an organic solvent. Preferably, methanol and ethyl acetate are used. However, other solvents, such as ethanol, butanol, ether, n-hexane. gasoline, toluene, acetone, methylene chloride, methyl ethyl keytone and t-butyl acetate are also conceivable. The combined extracts are concentrated to dryness under a vacuum. The contents of the extract are investigated with the help of HPLC-NMR-MS/MS-CD coupling. The crude product obtained is separated with the help of a chromatographic method. Preferably, vacuum liquid chromatography is used. However, other chromatographic procedures are also conceivable. Silica is used as stationary phase. However, the use of other stationary phases, such as aluminum oxide or cellulose or a separation by liquid chromotomography, such as NSCC, is also conceivable. A solvent gradient of two or more organic solvents is used. Preferably, methylene, chloride and methanol are used. However, other solvent mixtures, consisting of the combination of 2 or 3 of the following solvents, are also conceivable: ethanol, propanol, butanol, ether, n-hexane, gasoline, toluene, acetone, ethyl acetate, methyl ethyl ketone, T-butyl acetate. Different fractions are collected and analyzed for their content of inventive compounds. Preferably, the coupling of HPLC with NMR, MS/NMR MS/MS and CD spectroscopy directly in the mixture is used. Usually, the inventive compounds are obtained after the lipophilic components of the abstract. After the fractions in question are concentrated, the crude product is purified by means of a chromatographic method on a suitable support material with a solvent gradient. The semi-preparative HPLC, for example, is used as chromatographic method. The purification can also be accomplished by a recrystallization from a suitable solvent or solvent mixture.

Examples of Inventive Compounds

[0035] The invention is demonstrated by carrying out appropriate examples.

[0036] The fungus of the Penicillium sp. is isolated from freshly collected samples of the marine sponge Xestospongia exigua. Tissue samples are obtained from the inside of the sponge under sterile conditions and applied on malt agar slant culture. These slant cultures contain malt extract (15 g/L) as well as bay salt (24.4 g/L) and are incubated at 27° C. Pure strains of Penicillium sp. are isolated from the growing culture by re-inoculation on malt agar plates. Before the extraction, the fungi are grown in a malt broth medium (25 g malt extract and one liter of sea water. After 41 days of incubation, the mycelia and culture filtrate are collected and extracted with methanol and ethyl acetate. The combined extracts are concentrated to dryness under vacuum. Crude product is obtained in an amount of 6.31 g and chromatographed on silica gel with the help of liquid chromatography. A solvent gradient of methylene chloride and methanol is used. The lipophilic fractions 1 to 3 contain fatty acids and steroids and the inventive xestadecalactones are collected in fractions 4 to 6. The factions are concentrated and the crude products are purified by means of a semi-preparative HPLC (Merck) on a Eurospher C18 column with a methanol gradient of the following composition. 0 minutes 40% MeOH, 30 minutes 60% MeOH, 35-40 minutes 100% MeOH. Examples 1 to 3 are obtained.

Example 1

[0037] xestodecalatone A

[0038] colorless powder; [α]_(D) +28.3° (c 0.31, MeOH)

[0039] EIMS (70 eV) m/z [M]⁺ 264 (88), [M−H₂O]⁺ 246 (22)

Example 2

[0040] xestodecalatone B

[0041] colorless powder; [α]_(D) +22.5° (c 0.15, MeOH)

[0042] EIMS (70 eV) m/z [M]⁺ 280 (38)

Example 3

[0043] xestodecalatone C

[0044] colorless powder; [α]_(D) +17.3° (c 0.3, MeOH)

[0045] EIMS (70 eV) m/z [M]⁺ 280 (22)

[0046] Structure Clarification of the Claimed Compounds

[0047] The chemical structures of the claimed compounds are confirmed by modern spectroscopic methods, which include NMR spectroscopy, mass spectroscopy and CD spectroscopy.

[0048] Synthesis of the Claimed Decalactones

[0049] Aside from being isolated from biological material, the inventive compounds can also be produced by chemical synthesis from known starting materials. The inventive compounds are produced by the synthesis shown in outline A. The compounds are obtained as racemic mixtures. Alternatively, compound 5 can also be synthesized enantioselectively in any configuration by a selective reducing agent and used for the synthesis of 6. In this way, compound 9 can be synthesized in any possible configurations.

[0050] Procedure

Example 1

[0051] Synthesis of Xestodecalatone A

[0052] Outline of the Synthesis:

[0053] Synthesis of Carboxylic Acid 2

[0054] Methyl (3,5-dihydroxyphenyl)acetate 1 (1 g, 5.6 mmoles), 7 g of potassium carbonate and 7.5 mL of benzyl chloride are heated in 20 mL of acetone until reaction is completed. Subsequently, the inorganic salts are removed by filtration through Celite and the solvent is removed under vacuum. The remaining oily residue is dissolved in 40 mL of 2N sodium hydroxide and refluxed for 30 minutes and the aqueous phase, acidified with 10N sulfuric acid, extracted with toluene. The organic phase is evaporated to dryness and the residue is recrystallized from ethyl acetate and petroleum ether, 1.66 g (4.7 mmoles) of 2 being obtained. This represents a unit of 86%.

[0055] Reference: H. Gerlach, Helv. Chim. Acta 1977, 60, 3039-3044.

[0056] Synthesis of Methyl 5-hydroxyhexanoate 4

[0057] 5-Hydroxy hexanoic acid 3(1 g, 7.69 mmoles) is dissolved in 30 mL of methanol, mixed with a catalytic amount of sulfuric acid and heated until the reaction is completed. Subsequently, the solvent is removed under vacuum and the residue distilled under the vacuum of an oil pump, 870 mg (6.00 mmoles) of methyl 5-hydroxy hexanoate 4 being obtained. This represents a yield of 78%

[0058] Reference: Organikum

[0059] Synthesis of Racemic Methyl 5-Hydroxyhexanoate 5

[0060] Methyl 5-hydroxy hexanoate 4 (0.1 moles) is added at room temperature in portions with stirring to a solution of 0.04 moles of NaBH₄ in 120 mL of isopropyl alcohol and allowed to stand overnight, the reaction being completed in this time. Dilute hydrochloric acid is then added carefully until hydrogen is no longer evolved. The solution obtained is extracted 5 times with ether. The extract is dried with sodium sulfate and the solvent is distilled off.

[0061] Reference: Organikum

[0062] Synthesis of 6, analogous to F. Bracher, B. Schulte, Liebigs Ann./Recueil 1997-, 1979-1982.

[0063] (3,5)-Dibenzyloxyphenyl)acetic acid (2, 2.73 g, 7.84 mmoles) and oxalyl chloride (25 mL) are stirred at room temperature under nitrogen for 1 hour. The excess of oxalyl chloride is then removed by vacuum distillation. The residue is dissolved in anhydrous methylene chloride (100 mL), anhydrous potassium carbonate (19 g) and 5 (7.84 mmoles) are added and the mixture is stirred under nitrogen for 6 hours. The precipitate formed is removed by filtration and washed with methylene chloride. The combined filtrates are concentrated under vacuum and the residue is purified by flash chromatography (hexane/ethyl acetate, 8:2), the ester 6 being obtained in this manner

[0064] Synthesis of 7, analogous to F. Bracher, B. Schulte, Liebigs Ann./Recueil 1997, 1979-1982.

[0065] The compound 6 (6.4 mmoles) is dissolved in the anhydrous triamide of hexamethylphosphoric acid (HMPA, 30 mL) and powdered sodium cyanide (0.945 g, 19.3 mmoles, dried under vacuum at 170° C.) is added. The mixture is stirred for 12 hours at 75° C., then cooled and treated with 2M hydrochloric acid (100 mL, hot) and extracted with ethyl acetate (2×100 mL). The combined organic phases are washed with water, dried over sodium sulfate and concentrated under vacuum. The residue is purified by flash chromatography (hexane/ethyl acetate 8:2; then ethyl acetate/methanol 9:1), the desired acid 7 being obtained.

[0066] Synthesis of 8, analogous of H. Gerlach, Helv. Chim. Acta 1977, 60, 3039-3044

[0067] The carboxylic acid 7 (0.59 mmoles) was dissolved in 12 mL of a 2:1 mixture of trifluoroacetic acid and trifluoroacetic anhydride and kept for 2 hours at room temperature. Subsequently, the reagent was removed under vacuum and the residue distributed between benzene and 2N potassium bicarbonate. After the benzene layers were evaporated, the residue was recrystallized from a mixture of ethyl acetate and hexane.

[0068] Synthesis of 9, analogous to H. Gerlach, Helv. Chim. Acta 1977, 60,3039-3044

[0069] Dibenzyl ether 8 in 15 mL of a 1:1 mixture of tetrahydrofuran and methanol was shaken with 25 mg of 10% palladium on charcoal under hydrogen. The catalyst was filtered off, the solvent was removed under vacuum and the residue was recrystallized from a mixture of methanol and benzene.

[0070] Other routes are also conceivable for the synthesis of the inventive compounds.

[0071] Synthesis of Derivatives

[0072] By suitable chemical reactions, derivatives can be prepared from the new compounds of the class of decalactones, which have been isolated from the culture of the fungus of the Penicillium sp. These suitable chemical reactions are described in the chemical literature (Organikum, Houben-Weyl Method of Organic Chemistry). These reactions preferably are alkylation reactions, acylation reactions and benzylation of the hydroxy group in the compounds of Formula I. The oxygen atoms of the ketone and ester carbonyl groups may be replaced, for example, by sulfur.

[0073] The derivatization of the compounds of the general Formula I is confirmed by examples.

Example 1

[0074] O-Methyl Derivative

Example 2

[0075] O-Benzyl Derivative

Example 3

[0076] O-Acetyl Derivative

[0077] Biological Properties of the Claimed Compounds

[0078] The claimed compounds have interesting biological properties, which makes them suitable for use as active compounds in pharmaceuticals. In particular, the claimed compounds are to be used as agents against carcinoses and as anti-infective agents. The compounds and derivatives inhibit the reproduction of certain strains of yeast, such as C. albicans and, with that, have fungicidal properties.

[0079] Testing the Biological Activity

[0080] Testing the biological activity for prevention of the growth of tumor cells is accomplished with the help of conventional commercial XTT testing. For this purpose, different tumor cell lines, such as L 1210, SKOV3 and MCF-7 are used. The effect of the compounds on cell proliferation and, with that, on cell count is determined indirectly by means of their mitochondrial activity. This non-radioactive. colorimetric assay system is based on the test system of Scudiero et al., Cancer Res. 48 4827-4833, 1988. The basic reaction is the mitochondrial dehydrogenation of the yellow tetrazolium salt XTT into the orange formazan dye. The dehydrogenation takes place only in the active mitochondria and, with that, correlates with the number of living cells. The formazan dye formed is measured spectrophotometrically at 490 nm and subsequently quantified.

[0081] The compounds are used in concentrations of 0.003 μg to 3.16 μg per mL for the testing.

[0082] The anti-infective activity is tested by means of conventional and commercially obtainable test methods. 

1. The compounds of the general Formula I

wherein the R¹ group may be H, linear or branched C₁-C₆ alkyl, C₁-C₆ alkyl, mono-substituted or multi-substituted by C₆-C₁₄ aryl linear or branched carboxy C₁ to C₁₈ alkyl, linear or branched C₁-C₆ alkoxycarbonyl, linear or branched C₁-C₁₂ alkylcarbonyl, C₂-C₆ alkenyl C₂-C₆ alkinyl, linear or branched cyano C₁-C₆ alkyl or benzyloxy, 9-fluorenylmethoxy-carbonyl (Fmoc), triphenylmethyl (Tr) 2-(4′-pyridyl)ethoxycarbonyl (Pyoc)or diphenylmethylsilyl (DPMS), X may be O, S, NOH or NOR⁴, the R² group may be H, linear or branched C₁-C₆ alkyl, C₁-C₆ alkyl, mono-substituted or multi-substituted by C₆-C₁₄ aryl linear or branched carboxy C₁ to C₁₈ alkyl, linear or branched C₁-C₆ alkoxycarbonyl, linear or branched C₁-C₁₂ alkylcarbonyl, C₂-C₆ alkenyl C₂-C₆ alkinyl, linear or branched cyano C₁-C₆ alkyl or benzyloxy, 9-fluorenylmethoxy-carbonyl (Fmoc), triphenylmethyl (Tr) 2-(4′-pyridyl)ethoxycarbonyl (Pyoc)or diphenylmethylsilyl (DPMS), X may be O, S, NOH or NOR⁴, wherein R⁴ may be linear or branched C₁-C₆ alkyl, C₁-C₆ alkyl, monosubstituted or multi-substituted by C₆-C₁₄ aryl linear or branched carboxy C₁ to C₁₈ alkyl, linear or branched C₁-C₆ alkoxycarbonyl, linear or branched C₁-C₁₂ alkylcarbonyl, Y may be O or S and Z may be H or OR³, wherein R³ may be H, linear or branched C₁-C₆ alkyl, C₁-C₆ alkyl, monosubstituted or multi-substituted by C₆-C₁₄ aryl linear or branched carboxy C₁ to C₁₈ alkyl, linear or branched C₁-C₆ alkoxycarbonyl, linear or branched C₁-C₁₂ alkylcarbonyl, C₂-C₆ alkenyl C₂-C₆ alkinyl, linear or branched cyano C₁-C₆ alkyl or benzyloxy, 9-fluorenylmethoxy-carbonyl (Fmoc), triphenylmethyl (Tr) 2-(4′-pyridyl)ethoxycarbonyl (Pyoc)or diphenylmethylsilyl (DPMS).
 2. The compounds of Formula I of claim 1 as R and S enatiomer, as (R,R), (S,S) and (S,R) steroisomers, as well as in the form of all possible mixtures of steroisomers.
 3. The compounds of the general Formula I of claims 1 and 2, in which the linear or branched C₁-C₆ alkyl preferably is methyl, the C₁-C₆ alkyl, substituted by C₆-C₁₄ aryl, preferably is benzyl, the linear or branched C₁-C₁₂ alkylcarbonyl preferably is acetyl, the C₂-C₆ alkenyl preferably is allyl, the C₂-C₆ alkinyl preferably is ethinyl or propargyl and the linear or branched cyano C₁-C₆ alkyl preferably is cyanomethyl,
 4. A compound of the general Formula I of claims 1 and 2, especially xestodecalatone A, in which R¹, R² and Z represent H, and X and Y represent Z represents OR³, depending on the stereochemistry.
 5. A method for the synthesis or isolation of a compound of Formula I of claims 1 to
 4. 6. A method for the isolation of compounds of Formula I of claim 5 with the steps of culturing the fungus of the Penicillium sp., extracting a culture broth of the fungus of the Penicillium sp. with an organic solvent, purifying the extract, and separating and purifying the compounds of the general Formula I.
 7. A method for the synthesis of compounds of Formula I of claim 5 by means of a chemical synthesis of outline A.
 8. A method for the synthesis of a pharmaceutical formulation using a compound of Formula I for medicinal use in man or animal.
 9. A method for the preparation of a pharmaceutical using a compound of Formula I of claims 1 to
 4. 10. A compound of Formula I of claims 1 to 4 and its use as a pharmaceutical.
 11. A compound of Formula I of claims 1 to 4 and its use as a therapeutically active ingredient in pharmaceuticals as an anti-tumor agent.
 12. A compound of Formula I of claims 1 to 4 and its use as a therapeutically active ingredient in pharmaceuticals as an anti-infective agent.
 13. A compound of Formula I of claims 1 to 4 and its use as a therapeutically active ingredient in pharmaceuticals as a fungicide.
 14. A compound of Formula I of claims 1 to 4 and its use as a therapeutically active ingredient in pharmaceuticals for the treatment of to plasmodia or trypanosomes.
 15. The use of the compounds of Formula I of claims 1 to 4 as therapeutically active ingredients for the preparation of a pharmaceutical for the treatment of a disease in man or animal.
 16. The use of the compounds of Formula I of claims 1 to 4 as therapeutically active ingredients for the preparation of a pharmaceutical for the treatment of a carcinosis.
 17. The use of the compounds of Formula I of claims 1 to 4 as therapeutically active ingredients for the preparation of a pharmaceutical for the treatment of a disease, which is based on the rapid division of endogenous cells.
 18. A method for the treatment of carcinoses by administering an effective dose with at least one compound of Formula I of claims 1 to 4 to humans or animals. 